AB0273 INTERSTITIAL MATRIX DESTRUCTION IS A CENTRAL PATHOLOGICAL FEATURE OF RHEUMATOID ARTHRITIS
Authors: A. C. Bay-Jensen, S. Holm Nielsen, C. Thudium, M. Karsdal
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The interstitial matrix is the ground substance of all connective tissues, such as bone, skin, tendons, internal organs, and ligaments<sup>[1]</sup>. Type I collagen (COL1) is not only the most abundant protein, but also crucial for tissue integrity and stability as it act as the skeletal network of most organs. COL1 is organized in fibrils and connecting other extracellular matrix proteins to form a dynamic tissue. In bone, COL1 is 80% of the total protein amount and 95% of the total collagen amount, and thereby bone is by far the most COL1 rich tissue<sup>[1]</sup>. Matrix metalloproteinase (MMP) driven COL1 degradation is a central feature of in the pathogenesis of rheumatoid arthritis (RA) resulting in the release of C1M into the circulation. The common soluble biomarkers in RA are measures of inflammatory factors such as CRP, thus there is room for blood-based biomarkers reflecting tissue destruction. <h3>Objectives</h3> MMP-mediated tissue destruction may be a central part of inflammatory disorders, albeit overlooked. The biomarker C1M was developed more than a decade ago<sup>[2]</sup>. C1M originates from soft tissue turnover (from the action of MMP-2, -9, and -13<sup>2</sup>), not bone, thus very different from the bone degradation biomarker CTX-I. The aim was to review the literature to provide an overview on the potential context of use of assessing MMP-mediate COL1 degradation in RA, according to the FDA BEST guidelines<sup>[3]</sup>. <h3>Methods</h3> PubMed and google scholar were searched for full-text original articles in English using the keywords C1M, biomarker, and rheumatoid arthritis. The search period was set to 2011 to 2022, included. Also, we limited the included articles to those assessing blood levels of C1M in clinical RA samples and animal models, thus excluding articles assessing the biomarker assessed in cell cultures or in silico models. <h3>Results</h3> 396 titles were identified of which 14 were full text, English written articles. The figure provides the main conclusions of the 14 articles. C1M was 2-4 times elevated in patients with RA compared to healthy donors or to patients with undifferentiated arthritis (UA) and is increased in a rat model of RA (orange box). C1M release is inhibited by biologics, such as anti-IL6 receptor, anti-TNFs, and Jak inhibitors, and was shown to be associated with disease activity (blue box). C1M was predictive of treatment response (purple box) and associated with disease progression (green box). <h3>Conclusion</h3> MMP-mediated COL1 degradation was more than 100% elevated in RA, suggesting that tissue destruction is actively ongoing in these patients. Tissue destruction was prognostic for further joint damage. Only those treatments that strongly inhibited this tissue destruction was efficacious. In alignment, changes in tissue destruction were predictive for efficacy. <h3>References</h3> [1] Karsdal et al. Biochemistry of Collagens, Laminins and Elastin, 2019. [2] Leeming et al. Biomarkers 2011. [3] BEST (Biomarkers, EndpointS, and other Tools) FDA, US, 2016. [4] Siebuhr, et al. J Transl Med, 2012. [5] Drobinski, Arthr Res Ther, 2021. [6] Maijer et al. PLoS One 2016. [7] Bay-Jensen et al. BMC Rheumatol, 2019. [8] Gudmann et al. Clin Exp Rheumatol, 2018. [9] Burmester, et al. Ann Rheum Dis, 2017. [10] Thudium et al. Arthr Res Ther 22, 2020. [11] Gabay et al. RMD Open, 2018. [12] Taylor et al, Arthr Res Ther 21, 2019. [13] Kjelgaard-Petersen et al. Arthr Rheumatol, 2018. [14] Blair et al. Sci Rep, 2020. [15] Bay-Jensen et al. Arthr Res Ther, 2016. [16] Siebuhr et al. Arthr Res Ther 15, 2013. Blair et al. PLoS One, 2019. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Signe Holm Nielsen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Christian Thudium Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Morten Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience.